LYDMA-antigens and Immunity against EBV-infected Cells Epstein-Barr Virus as a Model for the Study of Host-infection Interaction

1987 ◽  
Vol 2 (2) ◽  
pp. 125-132 ◽  
Author(s):  
Maria L. Villa ◽  
Emilio Bombardieri
Keyword(s):  
Transcriptional Activation ◽  
Epstein Barr Virus ◽  
Dna Viruses ◽  
Barr Virus ◽  
Good Potential ◽  
Infected Cells ◽  
Membrane Antigens ◽  
Epstein Barr ◽  
Host Infection

Molecular biology has shown that DNA viruses carry their own transforming genes, unlike RNA viruses (retrovirus), which use cellular “oncogenes”. Some of the products of transforming viral genes are very good potential targets for immune defence. Epstein-Barr virus (EBV) immortalization is linked to the transcriptional activation of some latently transcribed regions; the lymphocyte-determined membrane antigens (LYDMA), the product of one of these regions, are the T-cell's chosen target. EBV-induced immortalization may therefore be free from any malignant consequence as long as immortalized clones are suppressed by immunosurveillance. In vivo, LYDMA-positive clones may be susceptible to immune control; LYDMA-negative clones can transform to neoplastic cells

Detection of lymphocytes productively infected with Epstein–Barr virus in non-neoplastic tonsils

Microbiology ◽  
2000 ◽  
Vol 81 (5) ◽  
pp. 1211-1216 ◽  
Author(s):  
Tetsuya Ikeda ◽  
Ryo Kobayashi ◽  
Manabu Horiuchi ◽  
Yoshifumi Nagata ◽  
Makoto Hasegawa ◽  
...  
Keyword(s):  
Epstein Barr Virus ◽  
Immune Surveillance ◽  
Lymphoid Tissues ◽  
Healthy Individuals ◽  
Barr Virus ◽  
Multiple Copies ◽  
The Face ◽  
Infected Cells ◽  
Epstein Barr

Epstein–Barr virus (EBV) persists for life in the infected host. Little is known about EBV reactivation and regulation of virus persistence in healthy individuals. We examined tonsils of chronic tonsillitis patients to detect EBV transcripts, EBV genomes and lytic proteins. LMP1 transcripts were observed in 11 of 15 specimens and BZLF1 transcripts were detected in six. Multiple copies of EBV genome equivalents per cell, and ZEBRA- and viral capsid antigen-positive cells were also detected in tonsillar lymphocytes. These results indicate that EBV productively infected cells may survive in the face of immune surveillance in the tonsils. Thus, EBV replication may occur in tonsillar lymphocytes, and tonsillar lymphoid tissues may play a role in the maintenance of EBV load in vivo.

scholarly journals The EBNA1 Protein of Epstein-Barr Virus Functionally Interacts with Brd4

2008 ◽  
Vol 82 (24) ◽  
pp. 12009-12019 ◽  
Author(s):  
Ammy Lin ◽  
Shan Wang ◽  
Tin Nguyen ◽  
Kathy Shire ◽  
Lori Frappier
Keyword(s):  
Transcriptional Activation ◽  
Epstein Barr Virus ◽  
Mitotic Chromosome ◽  
Human Cells ◽  
Host Proteins ◽  
Enhancer Element ◽  
Barr Virus ◽  
Chromosome Attachment ◽  
Infected Cells ◽  
Epstein Barr

ABSTRACT The EBNA1 protein of Epstein-Barr virus (EBV) is essential for EBV latent infection in ensuring the replication and stable segregation of the EBV genomes and in activating the transcription of other EBV latency genes. We have tested the ability of four host proteins (Brd2, Brd4, DEK, and MeCP2) implicated in the segregation of papillomavirus and Kaposi's sarcoma-associated herpesvirus to support EBNA1-mediated segregation of EBV-based plasmids in Saccharomyces cerevisiae. We found that Brd4 enabled EBNA1-mediated segregation while Brd2 and MeCP2 had a general stimulatory effect on plasmid maintenance. EBNA1 interacted with Brd4 in both yeast and human cells through N-terminal sequences previously shown to mediate transcriptional activation but not segregation. In keeping with this interaction site, silencing of Brd4 in human cells decreased transcriptional activation by EBNA1 but not the mitotic chromosome attachment of EBNA1 that is required for segregation. In addition, Brd4 was found to be preferentially localized to the FR enhancer element regulated by EBNA1, over other EBV sequences, in latently EBV-infected cells. The results indicate that EBNA1 can functionally interact with Brd4 in native and heterologous systems and that this interaction facilitates transcriptional activation by EBNA1 from the FR element.

Epstein-Barr Virus in Nasal Lymphomas Contains Multiple Ongoing Mutations in the EBNA-1 Gene

Blood ◽  
1998 ◽  
Vol 92 (2) ◽  
pp. 600-606 ◽  
Author(s):  
M.I. Gutiérrez ◽  
G. Spangler ◽  
D. Kingma ◽  
M. Raffeld ◽  
I. Guerrero ◽  
...  
Keyword(s):  
Epstein Barr Virus ◽  
Strong Support ◽  
Multiple Infections ◽  
Direct Role ◽  
Dna Viruses ◽  
Barr Virus ◽  
Normal Individuals ◽  
Rare Occasion ◽  
Epstein Barr

We have described 5 major subtypes of Epstein-Barr virus (EBV) based on variations in EBNA-1 sequences. These include P-ala (identical to the prototype B95.8 virus), P-thr, V-pro, V-leu, and V-val. Normal individuals often carry multiple EBV subtypes, the most common being P-ala, whereas EBV-associated tumors examined to date always contain a single subtype, which only on rare occasion is P-ala. The primary hypotheses that these observations generate are as follows: (1) Each of these EBV subtypes are naturally occurring, and in normal individuals the multiplicity of subtypes results from multiple infections. (2) EBV subtypes in normal individuals are generated in vivo from a single infecting virus subtype by mutations in EBNA-1. The second hypothesis essentially excludes the possibilities that the nonrandom association of certain subtypes with lymphomas is secondary to the geographic distribution of EBV subtypes and, if proven correct, could provide strong support for a direct role of EBV in tumorigenesis. In this report, we provide evidence for the latter hypothesis. We show that the P-ala EBV subtype present in most nasal lymphomas undergoes and accumulates multiple mutations consistent with the generation of variant species of EBNA-1 in vivo. This phenomenon is similar to the generation of quasispecies in RNA viruses and is the first description of in vivo generation of subtypes in DNA viruses. In RNA-based viruses, including human immunodeficiency virus and hepatitis C virus, the emergence of quasispecies is linked to replication infidelity and significantly influences disease processes through its effect on viral tropism, the emergence of viruses resistant to the host defenses or to therapy, and pathogenicity. The present data thus raise important questions relating to the mechanisms whereby these mutations are generated in EBV and their relevance to the pathogenicity of EBV-associated lymphomas.

Epstein-Barr Virus in Nasal Lymphomas Contains Multiple Ongoing Mutations in the EBNA-1 Gene

Blood ◽  
1998 ◽  
Vol 92 (2) ◽  
pp. 600-606 ◽  
Author(s):  
M.I. Gutiérrez ◽  
G. Spangler ◽  
D. Kingma ◽  
M. Raffeld ◽  
I. Guerrero ◽  
...  
Keyword(s):  
Epstein Barr Virus ◽  
Strong Support ◽  
Multiple Infections ◽  
Direct Role ◽  
Dna Viruses ◽  
Barr Virus ◽  
Normal Individuals ◽  
Rare Occasion ◽  
Epstein Barr

Abstract We have described 5 major subtypes of Epstein-Barr virus (EBV) based on variations in EBNA-1 sequences. These include P-ala (identical to the prototype B95.8 virus), P-thr, V-pro, V-leu, and V-val. Normal individuals often carry multiple EBV subtypes, the most common being P-ala, whereas EBV-associated tumors examined to date always contain a single subtype, which only on rare occasion is P-ala. The primary hypotheses that these observations generate are as follows: (1) Each of these EBV subtypes are naturally occurring, and in normal individuals the multiplicity of subtypes results from multiple infections. (2) EBV subtypes in normal individuals are generated in vivo from a single infecting virus subtype by mutations in EBNA-1. The second hypothesis essentially excludes the possibilities that the nonrandom association of certain subtypes with lymphomas is secondary to the geographic distribution of EBV subtypes and, if proven correct, could provide strong support for a direct role of EBV in tumorigenesis. In this report, we provide evidence for the latter hypothesis. We show that the P-ala EBV subtype present in most nasal lymphomas undergoes and accumulates multiple mutations consistent with the generation of variant species of EBNA-1 in vivo. This phenomenon is similar to the generation of quasispecies in RNA viruses and is the first description of in vivo generation of subtypes in DNA viruses. In RNA-based viruses, including human immunodeficiency virus and hepatitis C virus, the emergence of quasispecies is linked to replication infidelity and significantly influences disease processes through its effect on viral tropism, the emergence of viruses resistant to the host defenses or to therapy, and pathogenicity. The present data thus raise important questions relating to the mechanisms whereby these mutations are generated in EBV and their relevance to the pathogenicity of EBV-associated lymphomas.

scholarly journals The Epstein-Barr Virus LF2 Protein Inhibits Viral Replication

2008 ◽  
Vol 82 (17) ◽  
pp. 8509-8519 ◽  
Author(s):  
Michael A. Calderwood ◽  
Amy M. Holthaus ◽  
Eric Johannsen
Keyword(s):  
Transcriptional Activation ◽  
Epstein Barr Virus ◽  
Reference Strain ◽  
Latent Infection ◽  
Potent Inhibitor ◽  
Lytic Replication ◽  
Future Studies ◽  
Barr Virus ◽  
Infected Cells ◽  
Epstein Barr

ABSTRACT The switch from Epstein-Barr virus (EBV) latent infection to lytic replication is governed by two transcriptional regulators, Zta and Rta. We previously reported that the EBV protein encoded by the LF2 gene binds to Rta and can inhibit Rta activity in reporter gene assays. We now report that LF2 associates with Rta in the context of EBV-infected cells induced for lytic replication. LF2 inhibition of Rta occurs in both epithelial and B cells, and this downregulation is promoter specific: LF2 decreases Rta activation of the BALF2, BMLF1, and BMRF1 promoters by 60 to 90% but does not significantly decrease Rta activation of its own promoter (Rp). LF2 decreases Rta activation by at least two mechanisms: decreased DNA binding and interference with transcriptional activation by the Rta acidic activation domain. Coexpression of LF2 also specifically induces modification of Rta by the small ubiquitin-like modifiers SUMO2 and SUMO3. We further demonstrate that LF2 overexpression blocks lytic activation in EBV-infected cells induced with Rta or Zta. Our results demonstrate that LF2, a gene deleted from the EBV reference strain B95-8, encodes a potent inhibitor of EBV replication, and they suggest that future studies of EBV replication need to account for the potential effects of LF2 on Rta activity.

scholarly journals Epstein-Barr Virus Nuclear Antigen 2 Binds via Its Methylated Arginine-Glycine Repeat to the Survival Motor Neuron Protein

2003 ◽  
Vol 77 (8) ◽  
pp. 5008-5013 ◽  
Author(s):  
Stephanie Barth ◽  
Michael Liss ◽  
Marc D. Voss ◽  
Thomas Dobner ◽  
Utz Fischer ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Epstein Barr Virus ◽  
Cell Transformation ◽  
Survival Motor Neuron ◽  
Nuclear Antigen ◽  
Survival Motor Neuron Protein ◽  
Barr Virus ◽  
Epstein Barr

ABSTRACT Here we provide evidence that EBNA2 is methylated in vivo and that methylation of EBNA2 is a prerequisite for binding to SMN. We present SMN as a novel binding partner of EBNA2 by showing that EBNA2 colocalizes with SMN in nuclear gems and that both proteins can be coimmunoprecipitated from cellular extract. Furthermore, in vitro methylation of either wild-type EBNA2 or a glutathione S-transferase-EBNA2 fusion protein encompassing the arginine-glycine (RG) repeat element is necessary for in vitro binding to the Tudor domain of SMN. The recently shown functional cooperation of SMN and EBNA2 in transcriptional activation and the previous observation of a severely reduced transformation potential yet strongly enhanced transcriptional activity of an EBNA2 mutant lacking the RG repeat indicate that binding of SMN to EBNA2 is a critical step in B-cell transformation by Epstein-Barr virus.

Characterization of the Epstein–Barr virus BRRF1 gene, located between early genes BZLF1 and BRLF1

Microbiology ◽  
2000 ◽  
Vol 81 (7) ◽  
pp. 1791-1799 ◽  
Author(s):  
Carine Segouffin-Cariou ◽  
Géraldine Farjot ◽  
Alain Sergeant ◽  
Henri Gruffat
Keyword(s):  
Transcriptional Activation ◽  
Binding Sites ◽  
Epstein Barr Virus ◽  
Regulatory Elements ◽  
Barr Virus ◽  
Viral Genes ◽  
Epstein Barr

The switch from latency to a productive cycle in Epstein–Barr virus (EBV)-infected B cells proliferating in vitro is thought to be due to the transcriptional activation of two viral genes, BZLF1 and BRLF1, encoding two transcription factors called EB1 and R respectively. However, a third gene, BRRF1 is contained in the BZLF1/BRLF1 locus, overlapping with BRLF1 but in inverse orientation. We have characterized the 5′ end of the BRRF1 mRNA and the promoter, PNa, at which BRRF1 pre-mRNA is initiated. We show that although a single BRRF1 mRNA species is induced by 12-O-tetradecanoylphorbol 13-acetate/sodium butyrate in several EBV-infected B cell lines, in Akata cells treated with anti-IgG two BRRF1 mRNAs can be detected. Transcription initiated at the BRRF1 promoter was activated by EB1 but not by R, and EB1-binding sites which contribute to the EB1-activated transcription have been mapped to between positions −469 and +1. A 34 kDa protein could be translated from the BRRF1 mRNA both in vitro and in vivo, and was found predominantly in the nucleus of HeLa cells transfected with a BRRF1 expression vector. Thus there are three promoters in the region of the EBV chromatin containing the BZLF1/BRLF1 genes, two of which, PZ and PNa, potentially share regulatory elements.

scholarly journals The Intersection of Epstein-Barr Virus with the Germinal Center

2009 ◽  
Vol 83 (8) ◽  
pp. 3968-3976 ◽  
Author(s):  
Jill E. Roughan ◽  
David A. Thorley-Lawson
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Ebv Infection ◽  
Latently Infected ◽  
Infected Cells ◽  
Epstein Barr ◽  
Transcription Program

ABSTRACT The current model of Epstein-Barr virus (EBV) infection and persistence in vivo proposes that EBV uses the germinal center (the GC model) to establish a quiescent latent infection in otherwise-normal memory B cells. However, the evidence linking EBV-infected cells and the GC is only indirect and limited. Therefore, a key portion of the model, that EBV-infected cells physically reside and participate in GCs, has yet to be verified. Furthermore, recent experiments suggested that upon infection of GC cells the viral growth latency transcription program is dominant and GC functionality and phenotype are ablated, i.e., EBV infection is not consistent with GC function. In this study we show that in vivo, EBV-infected B cells in the tonsils retain expression of functional and phenotypic markers of GC cells, including bcl-6 and AID. Furthermore, these cells are physically located in the GC and express a restricted form of latency, the default latency program. Thus, the EBV default latency transcription program, unlike the growth latency program, is consistent with the retention of GC functionality in vivo. This work verifies key components of the GC model of EBV persistence and suggests that EBV and the GC can interact to produce the latently infected memory cells found in the periphery. Furthermore, it identifies latently infected GC B cells as a potential pathogenic nexus for the development of the EBV-positive, GC-associated lymphomas Hodgkin's disease and Burkitt's lymphoma.

scholarly journals Epstein-Barr Virus Small RNA (EBER) Genes: Differential Regulation during Lytic Viral Replication

1998 ◽  
Vol 72 (11) ◽  
pp. 9323-9328 ◽  
Author(s):  
Norbert Greifenegger ◽  
Michael Jäger ◽  
Leoni A. Kunz-Schughart ◽  
Hans Wolf ◽  
Fritz Schwarzmann
Keyword(s):  
Viral Replication ◽  
Epstein Barr Virus ◽  
Transcriptional Activity ◽  
Lytic Replication ◽  
Early Event ◽  
Transcriptional Level ◽  
Barr Virus ◽  
Infected Cells ◽  
Epstein Barr

ABSTRACT In every latently Epstein-Barr virus-infected cell the viral genes EBER-1 and EBER-2 are transcribed by polymerase III. In lytically infected cells in vivo the EBER genes could not be detected. However, in cell culture downregulation could not be confirmed, and hence the relevance of this shutdown to the replication of the virus was not clear. We assayed the transcriptional activity of the EBER genes by nuclear run-on assays with enriched lytically infected cells and demonstrated that EBER-1 and EBER-2 are differentially downregulated on the transcriptional level during the switch to lytic viral replication. This downregulation was an early event during the lytic replication of the virus.

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